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Hydrostannation of AlkynesMouad Alami, Abdallah Hamze, Olivier Provot

To cite this version:Mouad Alami, Abdallah Hamze, Olivier Provot. Hydrostannation of Alkynes. ACS Catalysis, Amer-ican Chemical Society, 2019, 9 (4), pp.3437-3466. �10.1021/acscatal.9b00482�. �hal-02394188�

Hydrostannation of alkynes

Mouad Alami,a* Abdallah Hamze,a Olivier Provota*

aUniv. Paris-Sud, BioCIS, CNRS, University Paris-Saclay, Equipe Labellisée Ligue Contre Le Cancer, F-92296 Châtenay-Malabry, France

*mouad.alami@u-psud.fr or olivier.provot@u-psud.fr

Abstract: In this review, we present an overview of hydrostannation of alkynes until the end of

2018. Mechanism of the tin hydride addition on a triple bond is discussed at the beginning of

this review in the presence of metal catalysts as Pd, Ru-based complexes, Lewis acids and under

radical conditions. Then, stereoselectivity as well as regioselectivity aspects of tin hydride

addition on the carbon triple bond is discussed using metal-catalysis, radical conditions or Lewis

acids. In each of these items, the reactions will be studied for terminal alkynes and then, for

internal alkynes. Applications of hydrostannation of alkynes using metal-catalysis is presented

in a variety of total syntheses with Pd, Mo, Rh and Ru-complexes to provide highly

functionalized vinyl stannanes derivatives as key-intermediates. Comparison with other

methods providing vinyl stannanes using metallostannation followed by protonation is

presented before the last section dealing with a summary of classical experimental conditions

used to achieve the hydrostannation of alkynes.

Keywords: hydrostannation, alkyne, catalysis, stereoselectivity, regioselectivity, tin

1. Introduction.

In view of the broad synthetic value of alkenylstannanes in organic

chemistry,1-4 particularly for chemoselective Csp2–Csp2 bond

formation through Kosugi-Migita-Stille cross-coupling,5,6 these

substrates have emerged as highly valuable intermediates in

organic synthesis. Numerous applications document the

advantageous use of alkenylstannanes, which allow for the mild

coupling with diverse electrophiles in the presence of sensitive

functional groups of all kinds, and their application in the synthesis

of a vast number of biologically active natural and unnatural

compounds.7-14 Consequently, the development of convenient

methods for forming Csp2–Sn bonds, especially in a catalytic

process, has been an important subject in modern synthetic

chemistry.

Although many methods exist for preparing alkenylstannanes (see

Comparison with Other Methods), the direct addition of a tin–

hydrogen bond across the carbon–carbon triple bond, namely

hydrostannation,15,16 is the most attractive one in view of the

formation of functional group-rich alkenylstannanes. These

products can be used in transition metal-catalyzed coupling

reactions for the stereoselective synthesis of di- and trisubstituted

olefins. From a synthetic point of view, addition of a tin hydride to

an alkyne can be achieved with efficiency and atom-economy. The

main drawbacks of the organotin compounds are their toxicity,17

their low solubility in water, and the difficulty in separating tin by-

products from nonpolar organic products.

As depicted in Scheme 1, three general ways are available to

achieve the addition of R3Sn–H across a C–C triple bond:

hydrostannation (i) with a transition metal catalyst; (ii) under

radical conditions using either 2,2’-azobisisobutyronitrile (AIBN),

triethylborane (BEt3) or ultrasound as initiators; and (iii) with a

Lewis acid, a protocol that is less widely used than the classical

transition metal-catalyzed or radical-induced processes, but

nevertheless leads to some significant results with respect to

stereoselectivity.

Scheme 1. Addition of R3Sn–H across a C–C triple bond:

hydrostannation.

Among various transition metal catalysts for hydrostannation of

alkynes, by far the most extensively developed are palladium

complexes, first reported in 1987.18 To date, this method

constitutes the most widely used procedure and has been the

subject of several reviews.15,16,19 In comparison with radical

reactions or those promoted by a Lewis acid, the palladium-

catalyzed hydrostannation generally proceeds under much milder

conditions, resulting in higher yields of the products and excellent

syn-stereoselectivity.

Scheme 2. Hydrostannation of terminal and internal alkynes.

Control of both regio- and stereochemistry is the main issue in the

hydrostannation of alkynes, as in principle three different products

can be produced from terminal alkynes, and four different ones can

2 be formed from internal alkynes (Scheme 2). The product

distribution is dependent on the nature of the alkyne substrate (i.e.

terminal or internal), neighboring functional groups on the

substrate, as well as the reaction conditions used (presence of a

catalyst, solvent, additives, etc.). Of course, the challenge in this

process is the ability to produce an alkenylstannane as a single

isomer, which is a daunting task with an internal alkyne.

Stereochemical control has been achieved by employing catalytic

amounts of a transition metal complex, which allows the

hydrostannation of alkynes to proceed mainly in a syn-fashion (cis-

addition) as a consequence of the reaction mechanism. Very recent

advances, however, demonstrate that depending on the catalyst

used, the addition of the Sn–H bond may also occur with almost

complete anti selectivity. With respect to regiochemical control,

the hydrostannation reaction appears to be highly dependent on the

alkyne. The use of symmetrical alkynes as substrates greatly

simplifies many of the synthetic issues, but allows limited

structural flexibility. With unsymmetrical alkynes, directing

groups are routinely employed to avoid the formation of

constitutionally isomeric mixtures. This directing ability may

involve steric, electronic, or chelating influences. Figure 1

highlights the orientation of tin hydride in the addition to a carbon–

carbon triple bond in different situations, which is dictated by the

substitution pattern on the alkyne substrate.

Figure 1. Factors governing the regioselectivity for alkyne

hydrostannation.

The literature covered by this review has been surveyed through

the end of 2018. The review summarizes the most significant

advances in Csp2–Sn bond formation through tin hydride addition

to alkynes under transition metal catalysis, radical-induced

processes, and Lewis acid-promoted reactions. Many of these

reactions have been reviewed.20-22 However, some reviews are

more general, covering not only alkynes as substrates but also

other C–C multiple bond systems, together with other type of

addition processes such as hydrosilylation, hydroboration,

metalometalation, etc. Although palladium complexes represent

by far the most extensively used catalysts, this review also

highlights synthetically useful protocols using other transition

metal catalysts that constitute valuable alternatives to the

established palladium catalyst systems. Whenever possible,

comparison with palladium-catalyzed transformations will be

presented.

As previously mentioned, regio- and stereocontrol are two key

issues to be addressed in the hydrostannation process. Because the

reaction selectivity exhibits a marked sensitivity to the alkyne

substrates as well as to experimental conditions, this review

surveys the influence of proximal (hetero)-functional groups

attached to the C–C triple bond on the crucial issue of regio- and

stereocontrol in tin hydride addition. This part is organized by the

type of hydrostannation reaction involved (metal-catalyzed tin

hydride addition, radical-induced process, and Lewis acid-

promoted reaction), by reactivity patterns and by functional groups

within the alkyne substrates. In all sections, hydrostannation of

terminal alkynes is presented first, followed by reactions with

internal alkynes.

2.0 Mechanism and stereochemistry.

This section is intended to provide the practicing chemist with a

basic understanding of the currently accepted mechanisms to aid

in the rational selection and optimization of reaction conditions.

2.1 Palladium catalysis.

The palladium-catalyzed hydrostannation of alkynes18 constitutes

the most widely used procedure for the synthesis of E-

alkenylstannanes. Despite much effort in this field, the mechanism

of this reaction is probably the least understood metalloid-hydride

addition to alkynes because no kinetic study is available. Much has

been assumed mechanistically on the basis of the distribution of

products observed in the hydrostannation of alkynes and related

substrates. The reaction proceeds with exclusive syn-addition,

producing the -E-adduct and the -isomer (Scheme 3). The

regiochemistry of addition is controlled by many factors, of which

the structure of the alkyne substrate plays a critical role.

Scheme 3. Palladium-catalyzed hydrostannation of terminal

alkynes.

Hydrostannation reaction may be achieved using a Pd(0) or a

Pd(II) catalyst. In this latter case, the Pd-complex is reduced to

Pd(0) by R3SnH15,23 The palladium-catalyzed hydrostannation is

believed to take place through oxidative addition of R3Sn–H to a

14-electron L2Pd(0) species, formed by reduction of various

palladium-(II) complexes with R3SnH, to generate a Pd(II)–

hydrido stannyl intermediate 1 (Scheme 4).15,16 Subsequently,

reversible coordination of the alkyne with a vacant orbital on the

metal atom, followed by addition of the coordinated palladium–

hydride bond of 2 into the alkyne -bond delivers complexes 3a

and/or 3b. As shown in Scheme 4, two competing pathways may

be involved in this process. Hydropalladation would lead to

complex 3a, whereas stannylpalladation18,24 would deliver

alkenylstannane complex 3b. Finally, reductive elimination of

palladium from either 3a or 3b would afford the -E-

alkenylstannane and regenerate the palladium(0) catalyst.

Scheme 4. Proposed Mechanism of the Pd-catalyzed

hydrostannation of alkynes.

The proposed in situ formation of intermediate 1 has been

supported by the isolation25 of cis Pd(II) hydrido trialkylstannyl

intermediate 4, facilitated by stabilizing the complex with bulky

bidentate phosphine ligands. It was shown that complex 4 reacts

further with Me3SnH, even at -120 °C, to yield complex 5 and

molecular hydrogen (Scheme 5).

Scheme 5. Isolation of cis Pd(II) hydrido trialkylstannyl

intermediate 4 and its reaction with Me3SnH.

Questions persist about the possibility that a Pd(II) hydrido stannyl

intermediate 1 can undergo cis-addition of either the Pd–H

(hydropalladation) or Pd–Sn (stannylpalladation) bond to the

alkyne triple bond, and to date little convincing evidence exists to

distinguish between these pathways. Evidence in favor of the

hydropalladation pathway26 is available from a report on a

hydrostannation-cyclization sequence of 1,6-enynes 6 (Scheme 6).

In this process, the reaction begins by hydropalladation of the

triple bond of 6 (an alkyne is more reactive in Pd-catalyzed

hydrostannation than an alkene)26 to form intermediate 7, which

then undergoes an intramolecular carbopalladation leading to

species 8, followed by reductive elimination to produce exo-

methylenecyclopentane 9.

Scheme 6. Hydrostannation-cyclization sequence of 1,6-enynes 6.

As opposed to the behavior of 1,6-enyne derivatives, 1,7-enyne 10

does not lead to ring formation, likely because the

carbopalladation step for the construction of six-membered rings

may be unfavorable because of the size of the chelate formed when

the olefin coordinates to the palladium. Instead, the reaction

furnishes the internal alkenylstannane 11 (Scheme 7),26 a result

that is consistent with a mechanism involving a hydropalladation

pathway as depicted in Scheme 6.

Scheme 7. Pd-catalyzed hydrostannation of 10.

Another argument in favor of the hydropalladation pathway

(formation of intermediate 13 vs 14, Scheme 8) is the report

describing the palladium-catalyzed hydrostannation of terminal or

internal aromatic alkynes 12, in which the triple bond is

significantly polarized by the presence of a nitro group on the aryl

nucleus.27 Thus, the results depicted in Scheme 8 illustrate how

electronic differentiation of the C≡C triple bond can affect the

regioselectivity of the process, furnishing exclusively

alkenylstannanes 15 regardless of the nature of the R1 group (R1 =

H, C5H11, Ph). The overall preference for the formation of

tributylstannyl derivatives 15 is consistent with a mechanism

wherein tributyltin hydride formally acts as a hydride donor28 (Cf.

Alkynes with Electron-Withdrawing Substituents).

Scheme 8. Pd-catalyzed hydrostannation of p-NO2arylalkyne 12.

2.2 The particularity of [Cp*Ru]-based complexes in the

hydrostannation of alkynes.

In contrast to all other transition-metal-catalyzed hydrostannation

reactions documented in the literature, it was recently reported that

ruthenium complexes 16-1829-31 (Scheme 9) provide unique anti-

selectivity across various types of internal alkyne substrates to

afford (Z)-alkenylstannane product (Scheme 10).

Scheme 9. Ruthenium catalysts 16-18.

Scheme 10. Ru-catalyzed hydrostannation of alkynes.

A mechanistic hypothesis explaining this unique trans-

hydrostannation of symmetrical and unsymmetrical internal

alkynes in the presence of a transition metal has been reported by

Fürstner (Scheme 11).29,32,33 The proposed mechanism gives a new

lighting and complete the reaction mechanism proposed by Trosts

concerning his pionner work dealing with the trans-

hydrosilylation of di-substituted alkynes in the presence of

[Cp*Ru]-based complex (Cp* = 5-C5Me5).34 Firstly, the reaction

began with the coordination of the alkyne triple bond with the

electrophilic metal center of 16 to give intermediate 19 which then

favors a subsequent coordination of the tribubyltin hydride to

provide 20 in which the alkyne triple bond is supposed to act as a

four-electron donor. Then, subsequent inner-sphere hydride

delivery forms a metallacyclopropene intermediate 21 in which the

alkyne R1 group is oriented towards the bulky Cp* ligand.

Congested metallacyclopropene 21 may isomerize into 23 in a

reversible fashion in which the R1 substituent is further away from

the Cp* ligand. These steric factors are at the origin of the trans-

hydrostannation as a final reductive elimination of 23 via 24 places

the tin metal anti to the hydride leading to (E)-vinylstannanes.

Nevertheless, a concerted mechanism from 20 to 23 cannot be

totally excluded without the participation of an open cationic

4

Scheme 11. Proposed mechanism hypothesis explaining the trans-

hydrostannation of symmetrical and unsymmetrical internal

alkynes using Ru-complexe 16.

intermediate 22 as a hydride could be delivered from 20 to provide

a less congested metallacyclopropene 23.29,35 Mechanistic insights

explaining the stereo- as well as the regioselective outcomes of the

Bu3SnH trans-addition on internal alkynes having vicinal alcohols

or amines and using chloride pre-catalyst 17 are fully detailed and

reported.32,33

2.3 Radical conditions.

The radical-induced hydrostannation of alkynes has been

extensively studied and often affords regio- and stereoisomeric

mixtures of alkenylstannanes. The reaction follows a radical chain

mechanism involving trialkyltin radical addition to the C–C triple

bond to produce a mixture of alkenyl radicals (Scheme 9). 2,36-39

In this case, the initial regiochemistry is controlled by the relative

stability of the alkenyl radical species that gives rise to the

corresponding alkenylstannanes (the more substituted alkenyl

radical is favored). With respect to stereoselectivity, the initially

formed product from syn-addition (Z-adduct) is equilibrated to the

thermodynamically more stable E-isomer in the presence of tin

radicals under the reaction conditions.40 In general, the products

observed in radical hydrostannation often reflect thermodynamic

rather than kinetic selectivities because of the reversibility and

product isomerization through addition–elimination reactions.

Good stereoselectivities may be obtained if the equilibration

process leads to a product favored by other factors (often steric).

Recently, good syn selectivity furnishing the E-adduct has been

reported with the use of catalytic amounts of Et3B or

sonochemical initiation of the radical cycle. Regio- and

stereoselectivity of radical reactions can be predicted by radical-

stabilizing effects,41 and steric effects.2,42

Although this mechanism is widely accepted (Scheme 12), several

lines of evidence suggest that radical-mediated hydrostannation of

alkynes does not involve radical intermediates exclusively, but

more likely proceeds through a hybrid single-electron transfer

(SET)/radical propagation mechanism43 shown in Scheme 13.

Scheme 12. Proposed mechanism of the hydrostannation of

alkynes under radical conditions.

Recent reports highlight the crucial role played by molecular

oxygen in radical-mediated hydrostannation of alkynes employing

any radical initiator (e.g., AIBN, Et3B, etc). The O2-free AIBN-

mediated Bu3Sn–H addition to internal propargylic alcohols fails

to proceed, whereas the addition of even a trace of O2 into these

same reactions allows the hydrostannation to proceed readily. A

combination of control experiments, including the polar solvent

studies, deuterium-labeling studies, and DFT calculations provide

crucial insights into the mechanistic details of the hydrostannation.

Because the addition of Bu3Sn–H to a wide selection of alkynes

proceeds only in the presence of O2,44 and is faster in polar

solvents,45 it has been concluded that the reaction does not proceed

exclusively by a radical process. Instead, it is suggested to involve

the formation of cationic species 27 through O2-promoted single-

electron transfer (SET) oxidation of alkenyl radicals 26 (Scheme

13).

The stannyl radical 25 (Bu3Sn.) addition to the triple bond need

not be regioselective and will provide a constitutional mixture of

alkenyl radicals 26a,b. A SET from these radicals to O2 coalesces

to form the same three-centered alkenyl cation species 27 and

superoxide (O2

.–). Further hydride transfer from nBu3SnH

ultimately affords the Z-adduct under kinetic control and nBu3Sn+

28, which is rapidly reduced by superoxide to regenerate the chain

carrying radical Bu3Sn. Note that this mechanism has been

questioned as being inconsistent with other mechanistic studies

and computational data.46-48

Scheme 13. Proposed mechanism for the hydrostannation of

propargylic alcohols under radical conditions.

2.4 Lewis acid conditions.

Contrary to the standard radical-induced hydrostannation shown

in Scheme 12, the use of a Lewis acid such as ZrCl4 enables the

anti-addition of Bu3SnH, furnishing the Z-adduct with excellent

regio- and stereoselectivity.49 This outcome is general for terminal

alkynes and enyne derivatives. The reaction must be kept at 0 °C,

because both the yield and stereoselectivity decrease if the reaction

is carried out at room temperature. Indeed, Bu3SnH reacts with

ZrCl4 at room temperature to form a complex, which leads to a

rapid equilibrium between Bu3SnH, Bu2SnH2, and Bu4Sn.50 The

mechanism of this ZrCl4-catalyzed reaction (Scheme 14)50 is

claimed to proceed by coordination to the triple bond to produce

the -complex 29. Hydride transfer from Bu3SnH to an electron

deficient carbon from the side opposite to ZrCl4 stereoselectively

produces the pentacoordinate zirconium ate-complex 30. The

latter undergoes a transmetalation from zirconium to tin with

retention of configuration to afford a Z-adduct and regenerates

ZrCl4. It is noteworthy that ZrCl4 also catalyzes hydrostannations

with Bu2SnH2 to form regio- and stereodefined dialkenyltin

derivatives.50

Scheme 14. Proposed mechanism for the hydrostannation of

alkynes under Lewis acid conditions.

3 Scope and limitations.

3.1 Palladium-catalyzed hydrostannation of alkynes.

The primary challenge for hydrostannation of alkynes is the ability

to control both the regio- and stereochemical course of the tin

hydride addition. Since the discovery of transition metal-catalyzed

reactions, particularly with Pd-based systems, the stereoselectivity

in hydrostannation is largely predictable and proceeds

sterospecifically in a syn-fashion. The control of the

regioselectivity, however, remains a daunting task that depends on

the alkyne substrate and its neighboring functional groups (ester,

heteroatom, etc.). With such considerations in mind, this section is

organized according to the reacting alkyne (terminal and internal)

and then further subdivided according to nearby functional groups.

In addition, comments regarding the influence of the groups on tin

will be presented when appropriate.

3.1.1 Terminal alkynes.

3.1.1.1 Aliphatic Alkynes.

Unbranched linear alkyl-substituted alkynes have not been

extensively studied, and reactions with these substrates are usually

considered cumbersome under palladium catalysis. Oshima and

co-workers18 reported the first example of a palladium-catalyzed

hydrostannation of alkynes. Their studies revealed that in the

presence of a catalytic amount of Pd(PPh3)4, triphenyltin hydride

adds to 1-dodecyne to afford a mixture of isomers (31/32 = 11:89)

in which the -constitutional isomer 32 predominates (Scheme

15).

Scheme 15. Pd-catalyzed hydrostannation of dodec-1-yne.

Almost no selectivity (33a/34a = 57:43) is observed with 1-octyne

when using Bu3SnH instead of Ph3SnH and PdCl2(PPh3)2 as the

catalyst.28 However, increasing the steric bulk at the propargylic

position has a profound effect on the hydrostannation

regioselectivity. For example, the reaction of 3-pentyl-1-octyne

delivers a single compound, E- product 34b, in excellent yield

(Scheme 16).

Scheme 16. Pd-catalyzed hydrostannation of terminal alkynes.

Functional groups on alkynes can substantially modify the

regioselectivity through coordination of the metal center to

heteroatom groups.51 An early study52 describes attempts to

perform selective tributyltin hydride addition to a propargyl

glycine derivative 35. Despite an extensive survey of PdCl2L2

catalysts [L = PPh3, P(2-tolyl)3, PMe3, PBu3, dppe, AsPh3], the

reaction failed to achieve good yields of either constitutional

isomer 36 and 37 (Scheme 17).53 A later study54 demonstrates that

the use of a bulky electron-rich phosphine ligand, such as

Cy3P∙HBF4 in the presence of a catalytic amount of i-Pr2NEt leads

to selective formation of the -(E)-alkenylstannanes with

regioselectivities up to >99%. With Ph3P, these substrates show

much lower regioselectivities (Schemes 17 and 18). The role of

Hünig’s base is not obvious, but it has been speculated that it

minimizes the formation of the reduction by-product resulting

from protodestannylation processes.

Scheme 17. Pd-catalyzed hydrostannation of 35.

Scheme 18. Pd-catalyzed hydrostannation of undec-10-yn-1-ol.

Because organotin hydrides are expensive and are prone to

oxidation, strategies to generate such species in situ to perform

hydrostannations of alkynes have been reported. The use of either

Bu3SnCl/PMHS/KFaq or the combination of Bu3SnF, PMHS, and

catalytic amounts of tetrabutylammonium fluoride can serve as in

situ sources of tributyltin hydride for palladium-catalyzed

hydrostannation reactions.55

6

Scheme 19. Pd-catalyzed hydrostannation of terminal alkynes

using Bu3SnCl/PMHS/KFaq.

In agreement with a previous report,28 the regioselectivity remains

poor with alkyl-substituted alkynes, even for functionalized

substrates. Only hindered tert-butylacetylene affords excellent

selectivity for the -(E)-alkenylstannane (Scheme 19).

Propargylic alcohols constitute another class of aliphatic alkyne

substrates that have been particularly well exploited for the

formation of functionalized alkenylstannanes. The first

studies23,28,56 on the palladium-catalyzed hydrostannation of

propargylic alcohol and ether derivatives employed substrates

having no substitution at the propargylic position. An

approximately 60:40 mixture of - and -constitutional isomers is

usually obtained in the presence of Pd(PPh3)4 or PdCl2(PPh3)2

(Scheme 20). The use of modified stannanes such as

trineophenyltin [(PhMe2CCH2)3SnH]57 instead of Bu3SnH has no

significant effect on regioselectivity. However, changing the

catalyst and, in particular, the steric bulk of the ligands (e.g.,

Cy3P∙HBF4),54 leads to the opposite regioselectivity in favor of the

-(E)-constitutional isomer (/ = 30:70) probably because of

steric considerations. In summary, the results shown in Scheme 20

clearly illustrate how the selectivity is influenced by the steric bulk

of the phosphine ligand, whereas coordination factors appear to be

negligible because propargyl alcohols and propargyl ethers (e.g.,

silyl ether or benzyl ether) provide similar selectivities.

Scheme 20. Pd-catalyzed hydrostannation of propargylic alcohols.

As a general rule, increasing the steric bulk of the substituent at

the propargylic position provides better levels of -(E)-

alkenylstannane selectivity. Terminal secondary propargyl

alcohols23 and their corresponding ethers show some -(E)-

selectivity, whereas tertiary propargyl alcohols58 undergo highly

regioselective -(E)-hydrostannation (Scheme 21).

Scheme 21. Pd-catalyzed hydrostannation of congested

propargylic alcohols.

As mentioned previously, it should be noted that in the case of

secondary propargyl alcohols high selectivities to produce

synthetically useful -(E)-alkenylstannanes may be achieved by

using Pd2(dba)3/Cy3P∙HBF4/i-PrNEt2 (Scheme 22).54 These results

shown in Schemes 21 and 22, highlight the fact that steric effects

are the only determining factor in product selectivity under

palladium catalysis.

Scheme 22. Pd-catalyzed hydrostannation of secondary

propargylic alcohols.

Excellent regioselectivity for -(E)-isomer 39 may be achieved in

the hydrostannation of functionalized tertiary propargyl alcohol 30

performed with in situ-generation of R3SnH from R3SnCl and

PMHS as the reducing agent (Scheme 23).59 These conditions

avoid the handling of highly toxic Me3SnH and allow the

formation of alkenylstannanes 39a,b selectively without reduction

of the C–I bond.

Scheme 23. Pd-catalyzed hydrostannation of 38.

3.1.1.2 Aromatic alkynes.

A number of groups18,23,54,56,60,61Erreur ! Signet non défini. have studied the

hydrostannation of phenylacetylene under palladium catalysis. In

most reports, the reactions are not regioselective and an almost 1:1

mixture of - and -(E)-isomers is obtained employing Bu3SnH in

the presence of PdCl2(PPh3)254 or Pd(PPh3)4

56 (Scheme 24).

Performing the reaction with the catalytic system

Pd2(dba)3/Cy3P∙HBF4/i-PrNEt254 or using Ph3SnH18 give the -(E)-

adduct preferentially. These observations suggest the importance

of steric factors in controlling the regioselectivity of addition in

this substrate class.

In addition to steric effects, the nature and position of substituents

on the aromatic ring27,61,62 are also factors that play a crucial role

on the hydrostannation regioselectivity.

Scheme 24. Pd-catalyzed hydrostannation of terminal arylalkynes.

With 4-substituted phenylacetylenes bearing an electron-

withdrawing group (e.g., CO2Me, CN, CHO) the reaction

selectively furnishes the -isomer (Scheme 25). This outcome is

likely because of strong polarization of the carbon–carbon triple

bond resulting in addition of hydride to the more electron-deficient

-carbon of the acetylenic bond. This -regioselectivity decreases

upon substitution with an electron-donating group (e.g., R = 4-

OBn). However, under identical reaction conditions, switching the

electron-donating group from the para to the ortho position affords

exclusively the -branched styrylstannanes wherein the tin moiety

is delivered to the carbon proximal to the ortho-substituted aryl

nucleus. This ortho-directing effect (ODE)61,62 is general for

various terminal 2-substituted arylalkynes regardless of the

electronic nature of the ortho-substituent or its cordinating effect

because this trend is followed for simple alkyl substituents as well

(e.g., R = 2-Me).

Scheme 25. Pd-catalyzed hydrostannation of substituted terminal

arylalkynesand ortho-directing effect (ODE).

Furthermore, exclusive -regioselectivity is also observed with

sterically congested ortho,ortho’-disubstituted terminal aryl

alkynes (Scheme 26).63

Scheme 26. Pd-catalyzed hydrostannation of ortho,ortho’-

disubstituted terminal aryl alkynes.

Hydrostannation of heteroaromatic alkynes is poorly documented

with only the -stannylcupration of 2-ethynylpyridine in the

presence of water, (SnMe3)2, PtBu3 and Cu(OAc)2.64 During the

synthesis of Scalaridine A, a symmetrical bis-indole isolated from

the marine sponge Scalarispongia sp.,65 it was reported that

hydrostannation of 3,5-diethynylpyridine66 was achieved under

Pd-catalysis with a total -selectivity (Scheme 27).

Scheme 27. Pd-catalyzed hydrostannation of 2-ethynylpyridine.

3.1.1.3 Enynes.

With respect to -selectivity, the result obtained with 2-methyl-

substituted phenylacetylene (Scheme 25) is related to those

reported with terminal conjugated enynes 40 and 43 (Schemes 28

and 29). The Pd-catalyzed hydrostannation of hindered Z-enynes

40 is highly regioselective for the -isomers 41a,b even when the

alkene substituent is non-chelating (Scheme 28). However, an

extra stabilizing interaction between the oxygen atom and the

palladium center cannot be disregarded as a rationale for the -

Scheme 28. Pd-catalyzed hydrostannation of enyne 40.

Scheme 29. Pd-catalyzed hydrostannation of enyne 43.

regioselectivity (44:45 = 88:12) obtained with Z-enyne 43.

(Scheme 29). The corresponding E-isomer produces the -

constitutional isomer as the major product. Altogether, the results

shown in Schemes 25, 26, 29 clearly highlight how the presence

of conjugated olefins influence the regioselectivity of alkyne

hydrostannation.

3.1.1.4 Diynes.

Although very few examples of diyne hydrostannylation have

been reported, some basic information on steric and electronic

effects is apparent. Unsymmetrical terminal diyne 46 reacts

8 specifically at the terminal triple bond to give the -addition

product 47 chemo- and regioselectively (Scheme 30).23 Even when

including additional equivalents of tributyltin hydride, no further

hydrostannation of the remaining alkyne is observed, presumably

because of steric considerations. From these results it seems that

the presence of a second acetylenic group can exert a directing

effect on the hydrostannation selectivity.

Scheme 30. Pd-catalyzed hydrostannation of conjugated diyne

46.

The hydrostannation of 1,6-diynes provides additional support for

this hypothesis (Scheme 31).24 These substrates react with Bu3SnH

in the presence of Pd(OH)2/C through a

hydrostannation/cyclization sequence to furnish 1,2-

bis(methylene)cyclopentanes containing a tributylstannyl moiety.

The authors rationalize their findings by invoking the plausible

formation of a chelate (see Scheme 6) between the palladium

center and both alkyne groups prior to the cyclization. This

hypothesis is supported by experiments conducted in the presence

of strongly coordinating phosphine ligands, which preclude any

cyclization from occurring.

3.1.1.5 Alkynes with electron-withdrawing substituents.

In early reports23,56,68 on the hydrostannation of conjugated

alkynoic esters67 and alkynones, both substrates react with clean,

predictable regioselectivity. The overall preference for the

formation of -isomers is consistent with a mechanism wherein

tributyltin hydride formally acts as a hydride donor. With alkynoic

esters bearing a methoxycarbonyl group, the tributyltin hydride

addition across the C≡C triple bond provides exclusively the -

isomer.

Scheme 31. Pd-catalyzed hydrostannation of unconjugated diynes.

Conjugated alkynones23,68 also exhibit good to excellent

regioselectivity for the formation of the -isomer, but the level of

selectivity seems to depend on the nature of the tin hydride

employed. The reaction with Bu3SnH23 provided a 82:18 mixture

of - and -(E)-isomers whereas the use of Me3SnH68 furnishes

exclusively the -isomer (Scheme 32). Although the reaction with

Me3SnD is also regioselective, it is not stereoselective and

provides a 1:1 mixture of -(Z) and -(E)-isomers.69 Of note is the

chemical fragility of -tributylstannyl conjugated enones during

purification, leading to protodestannylation products. It is best to

use such products without delay following the hydrostannation

step.

Scheme 32. Pd-catalyzed hydrostannation of conjugated

alkynones.

3.1.1.6. Alpha-hetero substituted alkynes.

The presence of a heteroatom directly attached to the C≡C triple

bond should induce electronic perturbations of the alkyne and

therefore should impact the hydrostannation selectivity. Only a

few examples have been published concerning the palladium-

catalyzed hydrostannation of heterosubstituted terminal acetylenic

compounds. No doubt one reason for the paucity of data is the

comparative instability of 1-(dialkylamino)-1-alkynes and 1-

alkoxy-1-alkynes, making them difficult compounds to handle and

prepare.

The palladium-catalyzed hydrostannation of ethoxyethyne is not

regioselective70 and produces - and -(E)-isomers in a 58:42 ratio

(Scheme 33).23 In contrast to 1-(dialkylamino)-1-alkynes,

ynamides are more stable substrates and their reactivity has been

reported. The reaction of N-benzyl-N-benzoylaminoacetylene with

Bu3SnH gives an 85:15 mixture in which the -isomer

predominates.71 The pure -isomer can be easily obtained by

column chromatography on silica gel. The same authors72 later

found that the use of oxazolidino ynamides (Scheme 33) also

furnish the α-stannylated enamide but with a slightly diminished

selectivity (70:30). Interestingly, the replacement of the nitrogen

or oxygen atom on the triple bond with a sulfur atom has a

profound effect on the selectivity. Thus, the hydrostannation

works well with 1-phenylthioacetylene, leading to complete

regioselectivity in favor of the α-stannylated product (Scheme

29).73 It seems that the phenylthio moiety acts as an electron-

withdrawing group21 and polarizes the alkyne in a sense opposite

to that observed with alkoxyalkynes or ynamides. Of note, the

hydrostannation of alkynes with silicon substituents [e.g.,

(trimethylsilyl)acetylene] does not proceed with tributyltin

hydride in the presence of a palladium catalyst.23

Scheme 33. Pd-catalyzed hydrostannation of terminal alkynes

linked to a N or O-atom.

3.1.2 Internal alkynes.

3.1.2.1. Aliphatic alkynes.

Hydrostannations of dialkylalkynes have proven less satisfactory

than terminal aliphatic alkynes owing to diminished reactivity and

low regioselectivity. However, the presence of propargylic

heteroatom substitution enhances the reactivity. Reaction with

internal propargyl alcohols and ethers leads to more useful results

with respect to -regioselectivity than do simple dialkylalkynes.

The selectivity is influenced by the relative size of proximal

substituents, although some results suggest that neighboring

hydroxyl groups might have a directing effect.

With respect to steric bulk at the propargylic position, the results

shown in Scheme 34 clearly illustrate how the selectivity is

influenced by the steric differentiation of the two alkyne

substituents. With primary propargyl alcohols (e.g., but-2-yn-1-

ol), two constitutional isomers are obtained in fair yield (58%) and

a 25:75 ratio.58 Upon increasing steric bulk of the substituent at

C, the reaction gives high selectivity for the -alkenylstannanes.

Thus, the sec-butyl-substituted propargylic alcohol gives rise to a

single -adduct (>95:5) in 75% yield.74 Switching to propargylic

secondary alcohols, a different selectivity in favor of the -

constitutional isomers is observed and this -regioselectivity

increases with increasing steric bulk of the substituent at C.75

Scheme 34. Pd-catalyzed hydrostannation of internal propargylic

alkynes.

With diol-containing alkyne substrates, a propargylic primary

alcohol more effectively directs regioselectively than a secondary

alcohol function (Scheme 35).74 Better selectivities are obtained in

analogous hydrostannation reactions of the methyl- or silyl ether

compounds. The general trend in Scheme 35 is best explained by

a steric effect stemming from the substituent at the C position

reinforced by a cooperative OH-directing effect.

Scheme 35. Pd-catalyzed hydrostannation of functionalized

propargylic alcohols.

In the case of highly hindered propargylic substrates the

hydrostannation is slow, but the regioselectivity is high. A single

product is formed in which the tributyltin moiety is delivered to

the less sterically demanding C position (Scheme 36). The

replacement of polar solvents (e.g., THF, Et2O) by a hydrocarbon

solvent (e.g., hexanes), together with the use of Pd(OAc)2 or

Pd(TFA)2 in combination with the bulky tricyclohexylphosphine,

greatly enhances the hydrostannation efficacy (Scheme 36).76

Internal alkynes bearing sterically demanding substituents, such as

a cyclohexyl group, undergo hydrostannation at reduced rates even

when using large amounts (30 mol %) of Pd(TFA)2/Cy3P, which

has been shown to be as effective as Pd(OAc)2

Scheme 36. Pd-catalyzed hydrostannation of internal propargylic

esters.

3.1.2.2. Aliphatic aromatic alkynes.

In contrast to dialkylalkynes, the palladium-catalyzed

hydrostannation of aromatic alkylalkynes,23,62,77 is much easier to

achieve and does not require the presence of propargylic

heteroatoms for reactivity. In addition, the reaction is completely

regioselective delivering a single product (-isomer) suggesting

that aromatic rings are excellent directing groups probably for

electronic reasons. For example, 1-phenyl-1-heptyne62 or 1-4’-

methoxyphenyl-1pentyne78 are excellent substrates, giving a single

product (-isomer) in good yields (Scheme 37). However, this

regioselectivity decreases in the case of 1-phenyl-1-propyn-3-ol

( = 80/20), indicating a probable directing effect of the CH2OH

substituent (Scheme 37). Substituents on the aromatic ring have

interesting effects on reaction selectivity. Although meta and para

substituents have only a minor influence on regioselectivity, ortho

substituents, including non-chelating alkyl substituents (e.g., Me,

i-Pr), lead to extremely high selectivity for the same -(E)-

alkenylstannanes, clearly indicating that coordinating factors are

not the cause of this remarkable regioselectivity. This ortho-

directing effect (ODE) is general with several other substituted

arylalkynes. Highly hindered alkyl groups (e.g., R1 = 2-i-Pr) affect

the -distribution and enhance the -regioselectivity, thus

providing a single adduct in 66% yield.

Scheme 37. Pd-catalyzed hydrostannation of substituted

arylalkynes.

10 This effect is further illustrated in the hydrostannation of

sterically congested arylalkyne 48 having ortho/ortho’ methyl

substituents (Scheme 38).62 This result clearly highlights the role

of steric hindrance in directing the exclusive -addition of the

Bu3Sn group to the more hindered alkyne carbon atom (C).

Scheme 38. Pd-catalyzed hydrostannation of 48.

3.1.2.3. Aromatic and heteroaromatic alkynes.

Hydrostannation of alkynes with two different aromatic (or

heteroaromatic) rings has received less attention than aliphatic

aromatic alkynes probably because of the difficulties in controlling

the regioselectivity of the tin hydride addition. In the case of

substrates having a single electron-withdrawing group in the para

position of one ring, electronic effects prevail, and the palladium-

catalyzed hydrostannation formally proceeds by conjugate

addition of the hydride providing the -isomers (Scheme 38).27

This regioselectivity decreases upon substitution with an electron-

donating group. However, it is established that the presence of an

ortho substituent on an aromatic ring on one side of the alkyne

dictates the sense of regioselectivity. The hydrostannation

provides high selectivity for a single -isomer, regardless of the

electronic nature, coordinating ability or steric hindrance of the

ortho substituent (Scheme 39).27,63

The hydrostannation of highly hindered alkynes having

ortho/ortho’ substituents provides additional support for this

hypothesis. Thus, this ortho-directing effect has been successfully

extended to control the regioselectivity of ortho/ortho’

diarylalkynes 49 leading to a single constitutional isomer (Scheme

40).63,79 The regiocontrolled synthesis of alkenylstannane products

has been applied to subsequent cross-coupling chemistry to

provide selective access to diaryl- and triaryl-substituted olefins.79

Scheme 39. Pd-catalyzed hydrostannation of substituted

diarylalkynes.

Although the origin of this unique ortho directing effect is not

immediately clear, it was observed that ortho substituents,

regardless of their electronic properties, induce chemical shift

perturbations of the ethyne carbon atoms. The 13C NMR signal of

the -sp-carbon appears at higher field relative to the -carbon for

all ortho-substituted diarylalkynes.27,81 In addition, DFT

calculations81 and theoretical NBO (Natural Bond Orbital) /NCS

Scheme 40. ortho-Directing effects (ODE) in tolans.

(Natural Chemical Shielding) studies82 reveal that the selectivities

obtained are not a result of the magnetic anisotropic effects due to

the ortho substituent, but rather, are the result of structural

perturbations of the ethyne carbon atoms induced by steric strain.

3.1.24. 1,3-Conjugated alkynes.

Trost et al.83 first reported the hydrostannation of internal 1,3-

enynes. To achieve high regiochemical control, enyne substrates

require the presence of an activating group (e.g., COOR) on the

carbon-carbon double bond in a manner analogous to that observed

with alkynyl esters (Scheme 41).

Scheme 41. Pd-catalyzed hydrostannation of electron-poor

internal enynes.

Inverting ester and alkyl groups on the double bond of enynes had

no influence on the -regioselectivity as (1E,3E)-2-

ethoxycarbonyl-3-tributylstannyl-substituted 1,3 dienes were

obtained as single isomers (Scheme 42).84

Scheme 42. Pd-catalyzed hydrostannation of internal enynes.

A similar trend in -regioselectivity was obtained with conjugated

enynes bearing a sulfonyl substituent on the double bond,

affording 1-sulfonyl-3-tributylstannyl-substituted 1,3-dienes.85

Other conjugated enynes also function well in regioselective

hydrostannations. In an initial study of chloroenynes as building

blocks for the synthesis of enediyne natural products such as

neocarzinostatin, it was found that the regioselectivity favoring the

-constitutional isomer is dependent on the alkyne substituent for

E-chloroalkynes, whereas the Z-chloro isomers exhibited

uniformly complete -stannane selectivity regardless of the nature

of the R substituent (Scheme 43).86

Scheme 43. Pd-catalyzed hydrostannation of (E) and (Z) enynes

and the origin of the (Z)-directing effect (ZDE).

Replacement of the chlorine atom of the enyne with an alkyl

group,86 gives the same trend with Z-enyne substrates high -

selectivity and E-enynes producing mixtures of products.87

Remarkably, this regiocontrol has been successfully extended to a

wide range of enynes,57,86,87 including those having a tri- or tetra-

substituted double bond. These results clearly suggest that the

regioselectivity of H–Sn bond addition to enynes is controlled by

the geometry of the double bond, the so-called Z-directing effect

(ZDE) rather than the electronic, steric, or chelating properties of

the substituents87 (Scheme 44). Although the exact origin of this

ZDE remains unclear, the factors governing this regioselectivity

would be close to those observed in the hydrostannation of ortho-

substituted arylalkynes (ODE). In a similar manner, it was

observed that switching from the E- to Z-enyne isomers induced

chemical shift perturbations (13C NMR) of the ethyne carbon

atoms, thus increasing the difference in the chemical shift of the

resonances (a steric compression shift) arising from the C-

Catom from 5.0 to 7.9 ppm.87 In sum, this study shows that it is

possible to predict the major (or exclusive) -isomer formation

when a substituent (regardless of its nature) and the alkyne are on

the same side of the double bond.

Scheme 44. Pd-catalyzed hydrostannation of (E) and (Z) enynols.

In a more direct route to the dienediyne system related to

neocarzinostatin,88 this Z-directing effect has been extended to

include various symmetrical enediyne substrates in which the

presence of a second triple bond on the Z-double bond dictates the

sense of the regioselectivity (Scheme 45).89 Even on addition of

further equivalents of tin hydride, no further hydrostannation of

the remaining alkyne is observed, presumably because of steric

constraints. Notably, the reaction with the corresponding E-

isomers furnishes a mixture of -isomers. With unsymmetrical

silyl-enediynes, the two triple bonds exhibit appreciably different

reactivities toward Bu3SnH. Chemo- and regioselective

hydrostannation furnishes exclusively the -addition product

(Scheme 45).

Scheme 45. Pd-catalyzed hydrostannation of (Z)-enediynes.

Among other conjugated alkynes studied, 1,3-diynes are also

suitable substrates for chemo- and regioselective

hydrostannation.23

The presence of a second alkyne group seems to exert a directing

effect on the reaction selectivity (Scheme 46). In the case of silyl-

1,3-diyne derivatives, the TMS group block the hydrostannation

as discussed previously.

Scheme 46. Pd-catalyzed hydrostannation of conjugated internal

diynes.

3.1.2.5. Alkynes with electron-withdrawing substituents.

Conjugated internal alkynes are a generally reliable substrate class

under palladium catalysis and their hydrostannation shows good

regioselectivity for the -addition product (Scheme 43). A number

of groups have studied the hydrostannation of alkynyl esters.23,90-

95 As shown in the following representative examples, electronic

effects prevail in controlling the hydrostannation regioselectivity,

and steric considerations play a lesser role (Scheme 47).90 In

contrast to alkynyl esters, alkynyl ketones are more challenging

substrates for selective hydrostannation because of unwanted

protodestannylation. This problem has been addressed by the use

of the more hindered trineophyltin hydride, which circumvents

many of the protodestannylation and isomerization problems that

plague reactions with tributyl- and trimethyltin analogues (Scheme

47).57,96

12

Scheme 47. Pd-catalyzed hydrostannation of alkynyl ketones.

The first hydrostannation of -CF3-alkynes under Pd-catalysis was

recently reported.97 Using Pd(PPh3)4, hydrostannation of -CF3-

alkynes led to (E)-vinylstannanes with a good to excellent -

priority (Scheme 48). Experiments achieved at various

temperatures revealed that the -regioselectivity was enhanced at

low temperatures with good yields.

Scheme 48. Pd-catalyzed hydrostannation of -CF3-alkynes.

3.1.2.6. Alpha-hetero and alpha-haloalkynes.

The palladium-catalyzed hydrostannation reaction of alkynes

bearing an electron-deficient heteroatomic group such as

sulfonyl98-100 or phosphonyl101 are also known. Excellent

regioselectivity for the -addition of the stannyl group is again

observed whatever the nature of the R substituent (Scheme

49).98,101 Hydrostannation of alkynyl sulfones in the ionic liquid

[bmim][PF6] gives rise to the -adducts.102 The advantages of the

ionic liquid compared to typical organic solvents (e.g., THF, C6H6)

include increased yields, higher regioselectivities, ease of product

isolation, and facile catalyst recycling.

The hydrostannation of chiral alkynyl sulfoxides has also been

reported (Scheme 50)103 and leads to high levels of -

regioselectivity when the reaction is carried out at low temperature

(-78 °C to rt over 3 h). The resulting 1-stannylalkenyl sulfoxides

have been used in subsequent cross-coupling reactions as a

selective access to stereodefined 2-sulfinyl diene derivatives.104

Other -hetero-substituted alkynes102,105-107 are good substrates for

regioselective hydrostannations. Phenylthioalkynes, for example,

add tin hydrides with high regio- and stereoselectivity, irrespective

of steric contributions or chelation abilities of the substituents

(Scheme 51).73 Interestingly, the triple bond of 1-trimethylsilyl-2-

phenylthioethyne is not deactivated by the presence of silicon, in

contrast to the deactivating effect observed in the case of

unsymmetrical silyl-enediyne and silyl-diyne derivatives. Similar

levels of -regioselectivity are observed in the case of -

selenoalkynes (Scheme 51).108

Scheme 49. Pd-catalyzed hydrostannation of alkynes bearing an

electron-deficient heteroatomic group.

Scheme 50. Pd-catalyzed hydrostannation of chiral alkynyl

sulfoxides.

A detailed study of the hydrostannation of 1-alkoxy-1-alkynes

demonstrates that the regioselectivity is controlled predominantly

by the steric bulk of the substituents on the triple bond. As shown

in Scheme 52,109 upon increasing the steric demand of the R1

substituent, the proportion of the -constitutional isomer

increases.

Scheme 51. Pd-catalyzed hydrostannation of thio- and

selenoalkynes.

Scheme 52. Pd-catalyzed hydrostannation of 1-alkoxy-1-alkynes.

The resulting alkoxyalkenylstannanes are highly unstable toward

purification, and the chromatographic lability of the -

constitutional isomer serendipitously allows easy isolation of the

-isomer.

It is worth noting that internal ynamides can be subjected to

palladium-catalyzed hydrostannation. The best isomeric ratios are

obtained with oxazolidinyl ynamides. In this case, intramolecular

coordination of the carbonyl oxygen atom to the metal center could

favor the formation of the -isomer (Scheme 53).110

Scheme 53. Pd-catalyzed hydrostannation of oxazolidinyl

ynamides.

The stability and chemical properties of alkynyl halides vary

broadly depending on the halogen. In contrast to alkynyl fluorides,

alkynyl chlorides, bromides and iodides are relatively stable

species.111 Hydrostannation of 1-bromoalkynes, including

silylated 1-bromoalkynes, leads to selective formation of the

corresponding E-alkenylstannanes with only trace amounts of the

Z-isomers.23 This finding is further extended to a broad range of 1-

bromoalkyne substrates giving good yields and selectivities for the

desired -E-isomer (Scheme 54).112

Scheme 54. Pd-catalyzed hydrostannation of bromoalkynes.

To be successful, the reaction requires the use of 2 equiv of

Bu3SnH. The first equivalent of hydride adds to the triple bond and

the second equivalent is used to achieve palladium-catalyzed C–

Br bond cleavage through an alkylidene carbenoid intermediate.

This mechanistic proposal involving a hydrostannation-reduction

sequence is supported by the isolation of 1-chloro-1-

tributylstannyl alkene 50 when 1-chloro-oct-1-yne is subjected to

tributyltin hydride under palladium catalysis (Scheme 55).23 In this

case, no reduction of the C–Cl bond is observed upon the addition

of further equivalents of hydride. Alltogether, hydrostannation of

1-bromoalkynes constitutes a solution, albeit an indirect one, to the

problem of poor regiocontrol with unbranched linear terminal

alkynes.

Scheme 55. Pd-catalyzed hydrostannation of chloroalkynes.

3.2 Other metal-catalyzed hydrostannation reactions of

alkynes.

Apart from the predominant use of palladium catalysts in the

hydrostannation of alkynes, a number of other catalysts based on

Mo and Rh have been reported, in addition to a limited number of

examples using Ni, Co, Pt and Ru.113 Pioneering reports have

reported good comparative studies of various catalyst sources.

Among these transition metals, molybdenum has emerged as a

selective alternative to palladium if the -alkenylstannane isomer

is desired. A molybdenum complex of the type MoBr(-

allyl)(CO)2(MeCN)2 is a suitable catalyst for the hydrostannation

of terminal alkynes such as phenylacetylene and propargylic

alcohols via a clean syn addition, but without significant

regioselectivity.23 In contrast to palladium complexes, the use of

this Mo-based complex allows the hydrostannation of

trimethylsilyl acetylene, furnishing mainly the -vinyl stannane

adduct ( = 85/15).23

An important advance was the identification of the isocyanide

complex MoBI3 [MoBI3 = Mo(CO)3(t-BuNC)3], that exhibits

increased catalyst selectivity, turnover and stability.114 The tert-

butylisonitrile ligand was selected due to its steric bulk, with the

expectation that the large tert-butyl groups would influence the

regiochemical outcome of the reaction. Thus, using MoBI3

together with hydroquinone (to suppress radical hydrostannation),

useful -regioselectivities are observed for a wide range of

terminal propargylic substrates regardless of their substitution

patterns (Scheme 56).115 Efforts to tune the reactivity of

molybdenum catalysts by altering their structure have been

pursued. Investigation of the steric and electronic influence of the

isonitrile ligand reveals that the related phenyl derivatives [e.g.,

Mo(CO)3(PhNC)3] give comparable yields, although the

selectivities are lower than the tert-butyl derivatives in all cases

studied.116

Scheme 56. Mo-catalyzed hydrostannation of terminal alkynes.

In situ-generation of organotin hydrides, together with

molybdenum catalysts,117 afford similar levels of -

regioselectivity for several substrates.118 Excellent -selectivity in

the hydrostannation of propargylic substrates may be achieved

through the use of an (isonitrile)tungsten carbonyl complex of the

type W(CO)3(CNR)3, which gives comparable or even better

results than MoBI3 (Scheme 57).119

14

Scheme 57. Mo-and W catalyzed hydrostannation of terminal

alkynes.

In the molybdenum-catalyzed hydrostannation of terminal

alkynes,120,121 the addition mode of Bu3SnH has a strong effect on

the outcome of the reaction as it is believed that MoBI3 catalyzes

the decomposition of tributyltin hydride. Slow addition over 7 h

increases the yield, even if the amount of tributyltin hydride is

reduced to only one equivalent (Scheme 58).122

Scheme 58. Mo-catalyzed hydrostannation of functionalized

terminal alkynes.

As a class, alkynyl phosphonate123 and ester114,115 derivatives

exhibit excellent selectivity for the production of the -

alkenylstannanes with all substrates studied, independent of the

substitution pattern of the triple bond (Scheme 59).

Of note is the compatibility of the Mo catalyst toward an allyl

ester, which is incompatible with Pd(0) catalysis. In addition, high

chemoselectivity is achieved in the hydrostannation of a diynoic

ester having a terminal C–C triple bond (Scheme 59).114

Molybdenum-catalyzed hydrostannation of -heteroalkynes such

as ynamides124 is also highly regio- and stereoselective, furnishing

exclusively the -isomer for a range of substrates (Scheme 60).

Scheme 59. Mo-catalyzed hydrostannation of functionalized

internal alkynes.

Several applications in subsequent tin-iodine exchange/cross-

couplings have been demonstrated. 1-Chloroalkynes125 are also

viable substrates. Whereas alkyl-substituted chloroalkynes give

comparable results, the corresponding phenyl derivative provides

a mixture of the two constitutionally isomeric products in a 70:30

ratio (the reaction does not go to completion, yield not given).

Scheme 60. Mo-catalyzed hydrostannation of chloro and amino

terminal alkynes.

Very recently, a molybdenum-based pre-catalyst system (MoI2-

(CO)2(CNArDipp2)2 51; (ArDipp2)= 2,6-(2,6-(i-Pr)2C6H3)C6H3

featuring two encumbering m-terphenyl isocyanides ligands

was used to deliver (E)--vinylstannanes with an excellent

regioselectivity from a variety of terminal and internal alkynes

(Scheme 61).126 Under the conditions depicted in Scheme 61,

Pre-catalyst 51 converts phenylacetylene into the corresponding

(E)--vinylstanne with an excellent regioselectivity (: =

87/13) which is markedly superior to that of classical Pd

catalysts as PdCl2(PPh3)2 and Pd(PPh3)4; (: = 54/46) and (:

= 50/40), respectively.16 Terminal aryl alkynes having electron-

rich substituents (e.g. 4-Me; 4-OEt) were transformed into (E)-

-vinylstannes with regioselectivities greater than 91%. One

note that the presence of EWG on the phenyl ring as a 4-NO2

substituent is critical as the (E)--vinylstanne derivative

predominated. Internal alkynes are excellent substrates under

these conditions as (E)--vinylstannes were obtained with a

good regioselectivity ranging from 80 to 92%.Pre-catalyst 51

produced with a high regioselectivity (E)--vinylstannes

isomers using propargyl alcohols as substrates (: = 97/3 to

90/10), depending of substrates. These results clearly indicate

that pre-catalyst 51 impose strong steric constraints during

hydrostannation with a good to excellent discrimination.

Scheme 61. Molybdenum complexe 51-catalyzed

hydrostannation of alkynes.

Although Ni, Pt, and Co catalysts give poor regioselectivity (~

1:1), Rh catalysts [e.g., RhCl(PPh3)3] give good -selectivity

(~ 88:12) in the hydrostannation of phenylacetylene and

several propargylic ethers.60 The use of a cationic Rh complex

{e.g., [Rh(cod)2][BF4]} in the hydrostannation of propargylic

alcohols proceeds with very low regio- and stereoselectivity.

However, switching to allyl propargyl ether derivatives, the

reaction with Bu3SnH occurs selectively, delivering a single -

isomer adduct (Scheme 62)127 Under the same reaction conditions,

but using Et3SnH and Ph3SnH under otherwise identical reaction

conditions provides good yields but poor regio- and

stereoselectivities.

Other metals have also been employed for alkyne hydrostannation.

A copper-catalyzed reaction was reported with alkynyl esters.128

As in palladium-catalyzed reactions, only syn adducts are formed

in comparably good yields and in fact exclusive under catalysis by

[Ph3PCuH]6.

Scheme 62. Rh-catalyzed hydrostannation of terminal alkynes.

Even for the challenging case of an alkynyl ester bearing a bulky

Oi-Bu group, in which directing effects from steric and electronic

factors are working in opposition, the Cu-catalyzed

hydrostannation shows complete selectivity for the -adduct

(Scheme 63).129 With less electrophilic alkynyl amides,129 excellent

-regioselectivity is observed, but the reaction rate is very slow,

furnishing the -adduct in only 41% yield after 18 h (Scheme 63).

With this particular substrate, the Pd-catalyzed hydrostannation is

much more efficient. The catalyst [Ph3PCuH]6 is unreactive with

nonpolar alkynes such as diphenylacetylene. To circumvent the

need to separately prepare, isolate, and purify [Ph3PCuH]6, an

alternative protocol using a more common and convenient source

of copper for hydrostannation has been developed involving the

use of catalytic amounts of CuCl (10 mol %), potassium tert-

butoxide (10 mol %) and triphenylphosphine (15 mol %) in the

presence of tributyltin hydride (1.5 equiv). The reactions catalyzed

by the in situ-generated copper hydride provide alkenylstannanes

with similar yields and regioselectivities to hydrostannation

catalyzed by [Ph3PCuH]6.130

Scheme 63. Cu-catalyzed hydrostannation of alkynoates.

The reaction with the more challenging alkynyl ketones shows

high regioselectivity for -stannation, and no -isomer is

observed. In contrast to the syn-selective hydrostannation of

alkynyl esters, the major stannylated enone results from the anti-

addition of Bu3SnH.129 As shown in Scheme 64, syn- and anti-

additions appear to be governed in part by the steric demands of

the R2 substituent on the electron-withdrawing group.

Protodestannylation on silica gel chromatography of the product is

mainly responsible for the lower yields.

Scheme 64. Cu-catalyzed hydrostannation of ynones.

In the hydrostannation catalyzed by [Ph3PCuH]6, the excellent

regioselectivity observed is suggested to arise from polarization

of the acetylenic bond resulting in the addition of a stannylated

copper hydride (syn-hydrocupration, 52), to the more electron-

deficient -carbon of the triple bond. Subsequent transmetalation

of the resulting (E)-alkenylcopper 53 produces the

alkenylstannane. In the case of alkynones, the observed anti

addition has been rationalized by the isomerization from (E)-

alkenylcuprate 53 to (Z)- alkenylcuprate 55 through the formation

of allenoate species 54 (Scheme 65).129

Scheme 65. Plausible mechanism for the Cu-catalyzed

hydrostannation of ynones.

Among other metals employed for alkyne hydrostannation,

RuCl2(PPh3)4 gives good and complementary selectivities favoring

the -stannane product 57 (vs 56), but as a nearly 1:1 mixture of

E- an Z-isomers (Scheme 66).60

Scheme 66. RuCl2(PPh3)4-catalyzed hydrostannation of

phenylacetylene.

3.3 Ruthenium-Catalyzed trans-selective hydrostannation of

alkynes.

The pionner works concerning the hydrostannation of alkynes

using [Cp*-Ru]-based pre-catalysts highlighted the trans-

16 hydrostannation of symmetrical internal alkynes using the

cationic pre-catalyst 16.29 Under mild conditions (depicted in

Scheme 67), Fürstner showed that reaction is compatible with a

variety of functional groups and is applicable to substrates

containing esters, ketones, phthalimides, Weinreb amides, primary

tosylates, primary bromides, unprotected alcohols and acids

(Scheme 67).29

Scheme 67. Ru-complex 16 catalyzed trans-hydrostannation of

internal alkynes.

Hydrostannation of unsymmetrical internal alkynes in the

presence of cationic complex 16 provides exclusively the anti-

addition products, but as a mixture of -isomers. Replacement

of the cationic complex 16 by other Cp*-containing pre-catalysts

provides more satisfactory outcomes. For instance, the use of the

tetrameric cluster [Cp*RuCl]4 17 results in an almost exclusive

formation of a single -isomer resulting from an anti-addition

process.29 This trend in regioselectivity is found to be independent

of whether the propargylic alcohol site is primary, secondary, or

tertiary, suggesting that the reaction selectivity is not under steric

control.29,30 Reaction with the corresponding acetate derivative

results in a mixture of -isomers, clearly indicating that the

regioselectivity is intimately related to the presence of an

unprotected hydroxyl group. This Ru-catalyzed, anti-

hydrostannation is also successfully applied to internal alkynes

having a TMS group, 1-chloroalkyne substrates, as well as

terminal aliphatic alkynes, and in all cases studied, excellent -

regioselectivity is observed (Scheme 68).29

Scheme 68. Ru-complex 17 catalyzed trans-hydrostannation of

functionalized internal alkynes.

The hydrostannation of conjugated and non-conjugated diynes

(not showed) having a propargylic or homopropargylic alcohol

function were recently studied in the presence of pre-catalyst 17

(Scheme 69).131

Scheme 69. Ru-complex 17 catalyzed trans-hydrostannation of

conjugated diynes.

When the reaction was achieved at rt in DCM, trans-

hydrostannation of diynes having a propargylic alcohol function

furnished the -trans monostannylated adduct in equal proportion

with the distannylated product. Surprisingly, heating the mixture

at 80 °C in 1,2-dichloroethane led to monostannylated compounds

in good yields with only traces of distannylated compounds, even

by achieving with a larger excess of Bu3SnH. As a consequence, it

has been showed that achieving the hydrostannation by lowering

the temperature led a mixture of mono-and di-stannylated products

in which di-stannylated adducts predominated. It is interesting and

surprising to note that by achieving the reaction with diynes in the

presence of 17 and 2.5 equiv of Bu3SnH at -40 °C, distannylated

products were obtained as a mixture of regioisomers as the

hydrostannylation of the distal triple bond (C≡C is governed by

steric factors.131 It was also showed that pre-catalyst 17 was

effective to discriminate two triple bonds in non-conjugated diynes

in which a propargylic alcohols function is much more cooperative

for hydrostannation than a dialkyl alkyne or a protected (OTES)-

propargylic function.130

An equally pronounced effect is seen for acetylene carboxylate

derivatives most likely because of a steering mechanism that

echoes the results of the propargylic alcohol series. In the presence

of complex 17 (Scheme 70), an alkynyl carboxylic acid reacts with

high preference for stannation at the -position, suggesting a

cooperative effect between the protic functional group and the

catalyst. If this cooperativity with the protic functional groups is

lacking, the outcome is different. Thus, acetylenic esters exhibit

the opposite preference for the -stannane product (Scheme 70).

Scheme 70. Ru-complex 17 catalyzed trans-hydrostannation of

alkynoates.

In the case of internal aliphatic alkynes, complex 17 provides

similar results with respect to yield and -selectivity to those

obtained with complex 16. The efficiency of complex 17 is not

limited to aliphatic alkynes because carbonyl-conjugated alkynes

and internal aromatic alkynes offer similar high yields and

complete -selectivity for a range of substrates (Scheme 71).30

Scheme 71. Ru-complex 17 catalyzed trans-hydrostannation of

functionalized internal alkynes.

Under similar reaction conditions to those for internal alkynes,

terminal aromatic alkynes react with almost complete regio- and

stereoselectivity to give the corresponding E--alkenylstannanes

in high yields (Scheme 72).30 Notably, the ortho-substituent on the

aromatic ring does not play any role in the reaction

regioselectivity, contrary to what happens under palladium

catalysis (see Scheme 25). The regio- and stereoselectivity of

hydrostannation reactions using ruthenium complex 17 resembles

those in radical-mediated hydrostannation using AIBN or BEt3

initiators, but has clear advantages in reaction efficiency The

stable complex 17, under illumination by household fluorescent

light (30 W) at room temperature, generates a ruthenium hydride

species. The authors postulate that the reaction proceedes via a

radical pathway in which Ru–H species, rather than Bu3SnH,

donates a hydrogen atom to the alkenyl radical.30

Scheme 72. Ru-complex 17 catalyzed trans-hydrostannation of

terminal alkynes.

It should be noted that a global comparison of hydrostannation

with the relative hydrosilylation, hydrogermylation and

hydroboration will not be studied in this review, for lack of space.

However, various studies evoking these comparisons or showing

their complementarity have been reported.16,32,97,132

3.4 Hydrostannation under radical conditions.

The hydrostannation of alkynes under free-radical conditions is the

oldest and most reliable method for preparing alkenylstannanes. In

general, the reaction gives a mixture of stereoisomers. The

outcome is usually controlled by the stability of the radical

precursor that gives rise to the corresponding alkenylstannanes.

Radical hydrostannation of unsaturated bonds is not applicable to

all substrate types as discrimination between other sites of

unsaturation (e.g., alkyne vs alkene), or reduction (alkyne vs

halogen) in the molecule led to undesired side reactions.

Propargylic alcohols constitute an important substrate class that

offers good selectivity.133 The amounts of Bu3SnH employed with

respect to terminal propargylic alcohol and ether substrates

strongly effects the regio- and stereoselectivity of hydrostannation.

The use of a slight excess of Bu3SnH (1.3 equiv) together with

heating at 80 °C results in the formation of -(E)-alkenylstannanes

as the major isomers (Scheme 73).Erreur ! Signet non défini.

Scheme 73. Hydrostannation of terminal alkynols under radical

conditions.

The reaction selectivity strongly depends on the nature of the

terminal propargylic alcohol substrates employed (Scheme 74)134

Thus, under thermally initiated radical hydrostannation alkynol 56

provides -stannyl isomer 57, whereas protection of the alcohol as

its TMS derivative 58 leads to the formation of the kinetic (Z)--

alkenylstannane product 59. Unfortunately, rigorous identification

of product selectivity shown in Scheme 74 is not given.

Scheme 74. Hydrostannation of propargylic alkynols under radical

conditions.

Although disubstituted alkyl propargyl alcohols38,135,136 and

amines137 are reported to undergo highly regio- and stereoselective,

O-directed free-radical hydrostannation reactions, the high

temperatures necessary for the reaction (60 -120 °C) often cause

problems with functionalized substrates.Erreur ! Signet non défini.

However, triethylborane or 9-BBN138 constitute alternative radical

initiators active at low temperatures (room temperature to -78 °C)

which circumvent these drawbacks. The use of Ph3SnH in the

presence of a catalytic amount of Et3B provides good

stereoselectivity. Thus, phenylacetylene and trimethylsilyl

acetylene furnishes (E)--isomers exclusively under these

conditions (Scheme 75).37 Reactions with Bu3SnH and the same

terminal alkynes require longer reaction times, and the

corresponding alkenylstannanes are formed in lower yields.37

Scheme 75. Hydrostannation of terminal alkynes in the presence

of Et3B.

The selectivity of hydrostannation on internal alkynes initiated by

Et3B has been explored using bulky triorganotin hydrides.140

Selectivity for the (Z)-alkenylstannane from an anti-addition

process is often excellent (Scheme 76),141 although inversion of

selectivity can occur for substrates in which isomerization to the

thermodynamically more stable (E)-alkenylstannane is

facile.Erreur ! Signet non défini.40 Direct comparison of the Ph3SnH/cat.

Et3BErreur ! Signet non défini. and Bu3SnH/cat. Et3B methods with several

alkynes reveals that the Ph3SnH system is uniformly superior in all

respects for effecting an O-directed free radical hydrostannation

reaction. Not only does the Ph3SnH/cat. Et3BErreur ! Signet non défini.

combination more readily converts propargyl-oxygenated

disubstituted alkynes into (Z)-alkenylstannanes, it also delivers

products with improved stereo- and regiocontrol.

18

Scheme 76. Hydrostannation of functionalized internal alkynes in

the presence of Et3B.

A comparative hydrostannation study of Et3B and AIBN at 80 °C

reveals that in the case of internal propargylic alcohol

derivatives,142 the Et3B/air system promotes tin hydride addition

under very mild conditions with complete preference for the (Z)-

alkenylstannane. Furthermore, these conditions regioselectively

place the tin moiety on the alkyne carbon proximal to the oxygen

substituent. Conversely, in all cases employing AIBN,

approximately 1:1 mixtures of Z- and E-isomers are obtained.

Despite decades of acceptance, these observations suggest that the

hydrostannation mechanisms employing Et3B and AIBN appear to

be mechanistically distinct.

Given that Et3B autoxidizes rapidly in oxygen at room

temperature,143 recent studies highlight that the autoxidation

products of Et3B (borinic or boronic acids or esters) efficiently

promote hydrostannation of internal alkynes.144 This highly regio-

and stereoselective (Z/E = >99:1) radical-mediated and molecular-

oxygen (O2)-dependent hydrostannation works well with several

highly functionalized, primary propargylic alcohol derivatives

leading to (Z)-olefin products through anti-addition of Sn–H

across the alkyne (Scheme 77).

Scheme 77. Hydrostannation of internal propargylic alkynes in the

presence of B(OH)3 and EtB(OEt)2.

Remarkable differences in both regio- and stereoselectivity in

radical vs non-radical-mediated hydrostannation have been

reported. In radical-mediated hydrostannation there is a significant

steric effect on the selectivity of the hydrostannation of several

phenyl propargylic alcohols and silyl ethers when n-Bu3SnH and

Ph3SnH are compared. In all cases studied using n-Bu3SnH,

complete -regioselectivity is observed, resulting in products with

the tin moiety on the alkyne carbon proximal to the oxygen

substituent (Scheme 78).44 Contrary to the radical-mediated

transformation, the regiochemistry of the uncatalyzed addition

with n-Bu3SnH is completely reversed, as is the stereoselectivity

(exclusive syn-addition).

Scheme 78. trans-Hydrostannation of internal aryl propargylic

alkynes in the presence of Et3B.

The authors highlight that the uncatalyzed addition with n-Bu3SnH

gives a remarkable -regioselectivity irrespective of the electronic

nature of the aryl moiety (Scheme 79),44 whereas addition with

Ph3SnH appears to be driven by the electronic nature of the

arylalkynes.

Scheme 79. Hydrostannation of substituted arylpropargylic

alcohols.

A study with various trifluoromethyl arylalkynes with Bu3SnH

initiated by Et3B reveals good selectivity for the anti-addition

(Scheme 80).145 Although the reaction may be conducted under

transition metal catalysis, the best results are obtained under

radical conditions. Unfortunately, an alkyl derivative displays

significantly diminished yield and isomeric purity.

Scheme 80. Hydrostannation of -CF3 arylalkynes in the presence

of Et3B.

Sonochemical generation of tin radical species and subsequent

hydrostannation reactions can be initiated at low temperatures,

even below 0°C.146,147 Thus, reactions of excess terminal alkynes

(5 equiv) with triphenyltin hydride under an argon atmosphere

result in good to excellent yields of the alkenylstannane products

with very high kinetic (Z)-selectivity (Scheme 81).

Scheme 81. Hydrostannation of terminal lakynes under

sonication.

Free-radical hydrostannation of alkynylboranes has been

reported.148 Boryl substituents play a major role in the course of

these reactions, such that only attack at the β-position is observed.

In addition, careful choice of the boron substituent and

experimental conditions allow the stereoselective preparation of

pure Z- or E-isomers (Scheme 82).149

Scheme 82. Hydrostannation of alkynylboranes under radical

conditions.

3.5. Hydrostannation under Lewis acid catalysis.

Pioneering studies established that excellent regio- and

stereocontrol for the (Z)--isomer may be achieved through the use

of ZrCl4-catalyzed anti-hydrostannations of terminal aliphatic and

aromatic alkynes, as well as 1-chloroalkynes (Scheme 83).49,50

Although the reaction results in high selectivity (>95:5), the

alkenylstannane compounds are isolated in moderate yields

because of their tendency to undergo protodestannylation

processes during purification.

Scheme 83. ZrCl4-catalyzed hydrostannation of alkynes.

This ZrCl4-catalyzed hydrostannation of alkynes is also useful for

the synthesis of divinyl tin derivatives by reaction with Bu2SnH2

(Scheme 84).50 As in the reaction using Bu3SnH, the

hydrostannation leads to anti-addition of Bu2SnH2, furnishing the

(Z)--isomer 60 with high stereoselectivity (Z/E = >95:5).

Scheme 84. ZrCl4-catalyzed hydrostannation of alkynes using

H2SnBu2.

Tris(pentafluorophenyl)borane is also an effective Lewis acid

catalyst for the hydrostannation of alkynes with tributyltin hydride,

prepared in situ from easily handled chlorotributylstannane and

triethylhydrosilane (Scheme 85).150 The reaction proceeds in a

regioselective manner with terminal alkynes, affording the -anti-

hydrostannation products almost exclusively. Studies on the

mechanism of B(C6F5)3-catalyzed hydrostannation of internal

propargylic alcohols reveal that hydride transfer from Bu3SnH to

B(C6F5)3 generates [n-Bu3Sn]+[HB(C6F5)3]-. The authors postulate

that both the tributylstannyl cation insertion and hydride delivery

by Bu3SnH could occur in a more synchronized manner.151

Scheme 85. B(C6F5)3-catalyzed hydrostannation of terminal

alkynes.

In a complementary fashion, the selective hydrostannation of

simple aliphatic terminal alkynes to provide the -isomer is

accomplished using the novel tin hydride system n-

Bu2SnIH/MgBr2∙OEt2 (Scheme 86).152 Notably, no -isomer is

formed if n-Bu2SnIH is used alone, and hydrostannation of 1-n-

dodecyne gives an almost 1:1 mixture of -(E) and -(Z)-isomers.

The authors suggest the in situ formation of a pentacoordinated tin

hydride complex, [MgBr]+[n-Bu2SnBrIH]－, the structure of which

has been suggested by 119Sn NMR spectroscopy.

Scheme 86. MgBr2·OEt2 -catalyzed hydrostannation of terminal

alkynes in the presence of Bu2SnIH.

Other dialkyltin hydride halides have recently been introduced as

Lewis acidic hydrostannation reagents.138,153,154 Among them,

Bu2Sn(OTf)H, easily prepared from Bu2SnH2 and TfOH, is

valuable for the highly regio- and stereoselective hydrostannation

of various terminal and internal propargylic alcohols (Scheme 87).

Scheme 87. Hydrostannation of propargylic alcohols using

Bu2Sn(OTf)H followed by nBuLi.

3.6 Miscellanous methods.

In 2018, a metal- and Lewis acid-free method was reported for the

trans-hydrostannation of terminal and internal alkynes catalyzed

by a trityl cation155 (Scheme 88). A screening of reaction

conditions revealed a dramatic influence of the solvent, reaction

time and reactional temperature. n-Pentane was used as solvent to

avoid or reduce the formation of by-product n-Bu4Sn. Moreover,

it was showed that Z-to-E isomerization and decomposition

occurred at prolonged time. Variously substituted terminal

arylalkynes as well as terminal alkylalkynes were good substrates

under the experimental conditions depicted in Scheme 88 and were

rapidly transformed in Z-vinylstannanes in good yields with

remarkable regioselectivities and excellent stereoselectivity.

Similarly, di-substituted alkynes as 3-phenyl-prop-2-yne, ethyl 3-

phenylpropiolate and diethyl but-2-ynedioate were successfully

transformed into (Z)-vinylstannanes with a total stereo and

regioselectivity. It is suggested that the mechanism evolves by a

stannilinium cation intermediate formed by a hydride abstraction

of Bu3SnH by the trityl cation. Then hydrostannane adds anti

across the triple bond to furnish a stabilized bridged -vinyl cation

which is selectively reduced by Bu3SnH in a trans manner for

steric considerations.In contrast, is it of note that propiolic acid

methyl ester (bottom of Scheme 88) added Bu3SnH in a trans

20 manner but with reverse -regioselectivity to furnish the -

branched (Z)-ethyl-3-phenyl-3-(tributylstannyl) acrylate in a good

90% yield.

Schema 88. Trityl cation-catalyzed hydrostannation of various

alkynes.

Very recently, the first hydrostannation of phenylacetylene in the

absence of metal-catalysts, Lewis acids and any additives was

reported using tris(pentafloroethyl)tin ((C2F5)3SnH)156 (Scheme

89).

Scheme 89. (C2F5)3SnH-catalyzed hydrostannation of

phenylacetylene.

In contrast to metal-catalyzed hydrostannation of phenylacetylene

using trialkyltin hydrides as Bu3SnH, the reaction occurred in a

trans fashion and produced solely the (Z)-isomer with no trace of

the (E)-stereoisomer or the -branched vinyl stannane. The

stereochemistry and the regiochemistry of the (E)-isomer was

checked by NMR and X-ray analyses. However the impact of

substituents on regioselectivity has not yet been studied and

particularly with arylalkylalkynes having ortho-substituents for a

competitive study. One drawback in this methodology is the

instability of the electron-deficient tin hydride that oxidizes

rapidly to give hexakis(pentafluoroethyl)distannane and H2 as

soon as (C2F5)3SnH is not perfectly pure.

4. Applications to synthesis.

One of the noteworthy applications of the hydrostannation

reactions lies in the selective generation of alkenylstannanes,

which serve as vinyl anion synthetic equivalents as partners in

Stille couplings,157,158 or by transformation into vinyl halides and

further reaction with nucleophiles to afford stereodefined di- or tri-

substituted olefins.141,159-162 Cascade hydrostannation /cyclization

reactions for the synthesis of spirocyclic heterocycles have been

also reported.163,164

Hydrostannation reactions have also found frequent uses in natural

product synthesis, with some selected examples described in

general reviews.15,16 Although, free-radical hydrostannations have

been implemented in many syntheses of natural products,165,166

discussion in this section covers only some applications of

transition-metal catalyzed reactions as applied to the total

synthesis of natural products.

The palladium-catalyzed hydrostannation of internal propargylic

alcohol derivatives167 is used efficiently for the construction of the

polypropionate segment of Callystatin A, a highly cytotoxic

marine polyketide. Reaction with the primary propargylic acetate

61 followed by iodination gives the alkenyl iodide 62 in 81%

overall yield (Scheme 90).168

Scheme 90. Pd-catalyzed hydrostannation of 61.

A palladium-catalyzed hydrostannation of alkynyl esters91,169,170 is

used in a synthesis of 4-alkylidenebutenolactone 65, a substructure

of the carotenoids pyrrhoxanthin and peridinin. It is suggested that

in addition to electronic polarization of the acetylenic bond, the

presence of the neighboring isopropylidenedioxy group in 63 is

responsible for the formation of the single stereo- and

constitutional isomer 64 (Scheme 91).171 Further trans-

acetalization/trans-esterification and Stille coupling of 64

provides -alkylidenebutenolide 65 with the (Z)-configuration of

the exocyclic C=C double bond.

Scheme 91. Pd-catalyzed hydrostannation of 63.

Similarly, alkynyl amides are also suitable hydrostannation

substrates. Thus, hydrostannation of 66 allows the exclusive

formation of the alkenylstannane 67 in 85% yield. Stille coupling

of this fragment with diodide 68, followed in a late-stage by double

asymmetric intramolecular Heck reaction leads to the synthesis of

(–)-Quadrigemine C and psycholeine (Scheme 92).172

Scheme 92. Pd-catalyzed hydrostannation of 66.

Examples of the use of the hydrostannation of

(phenylthio)alkynes106 include the synthesis of the lactone core of

8-epi-griseoviridin. The authors nicely demonstrate that the

unsaturated nine-membered lactone 69 undergoes regio- and

stereoselective palladium-catalyzed hydrostannation to provide

pure alkenyltin lactone 70 (Scheme 93). Subsequent tin-iodine

exchange and palladium-catalyzed carbonylation deliver the

propargyl amide 71.173

Scheme 93. Pd-catalyzed hydrostannation of 69.

The problems associated with non-selective, palladium-catalyzed

hydrostannation174 of the advanced intermediate enyne 72 have

been remedied through the use of molybdenum catalysis. To

achieve the synthesis of (–) Borrelidin, a potent antimitotic and

antiangiogenic macrolide, the authors perform the alkyne bond

hydrostannation with Mo(CO)3(t-BuNC)3 as the catalyst.

Accordingly, the reaction gives a single consitutional isomer in

which the tin moiety is proximal to the carbonyl function. The

regioselectivity of this addition is influenced by the presence of the

carbonyl group; in a related experiment with a macrolide

containing an enyne-alcohol motif the hydrostannation is much

less regioselective. Subsequent iodination of the C–Sn bond

delivers the corresponding alkenyl iodide 73 in 54% overall yield

(Scheme 94).175

Scheme 94. Mo-catalyzed hydrostannation of 72.

Application of the molybdenum-catalyzed hydrostannation toward

a flexible synthesis of substituted, unsaturated amino acids has

been reported.176,177

The efficiency of molybdenum pre-catalyst 51 and its

accommodation towards complex molecular structure as

Mifepristone, a synthetic steroid that acts as a progesterone

receptor antagonist was reported126 (Scheme 95).

Scheme 95. Mo-complex 51-catalyzed hydrostannation of 61.

Using 1.05 equiv of Bu3SnH in the presence of 51 (2 mol %) in

C6D6 at rt for 30 min, Mifepristone was transformed into the (E)-

-vinylstannane with a (: =98:2) regioselectivity in a nearly

quantitative yield (98%).

A rhodium-catalyzed hydrostannation of terminal propargylic

alcohols has also been described in a synthesis of nicandrenone, a

member of a family of structurally complex, steroid-derived

natural products. Hydrostannation of substrate 74 with

Wilkinson’s catalyst, [RhCl(PPh3)3] provides alkenylstannae 75 in

a modest 47% yield but with good -selectivity (Scheme 96).14

This compound was later used as a coupling partner for the

installation of the side chain onto the steroid skeleton 76.

Scheme 96. Rh-catalyzed hydrostannation of 74.

During the completion of the total synthesis of Nannocystin Ax a

potent cytotoxic agent,178 the Fürstner group reported the

efficiency of the [Cp*RuCl]4 catalyst 17 for the trans-

hydrostannation of the polyfunctionalized propargylic alcohol 77

(Scheme 97). This transformation occurred cleanly to give 78 as a

single regio- and stereoisomer in a 80% yield. A further

methylation of the vinylstannane moiety of 78 followed by

methylation of secondary alcohol179 and reduction of the phenacyl

group by Zn, led to Nannocystyn Ax. As vinylstannane 78 was

obtained at the end of the synthesis, Fürstner used this opportunity

to prepare a panel of non-naturel analogues for a biological

evaluation.

Scheme 97. Ru-complex 17 catalyzed trans-hydrostannation of

77.

22 A variety of total syntheses using the trans-hydrostannation of

alkynes with comparisons of ruthenium-catalyzed and radical

conditions has been compiled very recently by the Fürstner’s

group.132,180,181

5.0 Comparison with other methods.

The classical approaches to the synthesis of alkenylstannanes are

the reactions of alkenyl metallic reagents with tin halides or the

condensation of a tin-metal compounds with electrophiles. In

addition to hydrostannation reactions of alkynes, there exists other

ways of forming an alkenyl–Sn bond from acetylenic substrates.

The more widely used methods include the stoichiometric

stannylcupration of alkynes and the catalytic stannylmetalation of

alkynes in the presence of a transition metal.64 Direct comparisons

among the various methods are rare,58,73 and they are further

complicated by the complexity of the number of factors impacting

the selectivity for a given transformation. Accordingly, only

general considerations are provided here.

Alkenylstannanes usually are prepared by the reaction of an

alkenyllithium or –magnesium reagents with trialkyltin chlorides.

In the case of elaborated substrates, this transformation requires

the stereoselective preparation of an alkenyl metallic reagent

through multi-step synthesis prior to the coupling with R3SnX,

thus generating waste. Because alkenyllithium or -magnesium

reagents are very often incompatible with labile functional groups,

this synthetic reaction is not suitable for obtaining functionalized

alkenylstannanes when compared to the hydrostannation-based

process. Another way to achieve the synthesis of alkenylstannanes

is the addition of Bu3Sn–M (e.g., Li, Mg) with a carbonyl

compound followed by an elimination step. This procedure is well

suited for the preparation of cyclic alkenylstannanes.182

The formation of alkenylstannanes from alkynes is possible by

other means, such as stannylmetalation,21 using bimetallic reagents

of the type R3Sn–MRn in which M = B, Al, Cu, Zn, Si, or Sn. A

noteworthy feature of these reagents is their low basicity. As a

consequence, stannylmetalation may be performed on alkynes that

contain functional groups such as hydroxyl, ester, amine, and

halide. Stannylmetalation20 of alkynes may be divided into two

categories: (1) stoichiometric stannylcupration and (2) catalytic

stannylmetalation in the presence of a transition metal (e.g., Cu,

Pd). Both processes lead to syn-addition of the bimetallic species

unless equilibration occurs. The main drawback of these processes

is the necessity to use stoichiometric amounts of both the metalloid

tin and another metal, thus generating waste from reagents.

Stoichiometric stannylcupration of alkynes64,183 followed by

protonation of the cuprate species is a complementary process to

the Pd-catalyzed hydrostannation of alkynes. Although the two

processes proceed with excellent cis-stereoselectivity, the

regioselectivity of the addition of stannylcuprates to alkynes is not

only dependent on the reaction temperature, proton sources, and

the temperature at which the reaction is quenched, but also on the

structure of the alkyne and the nature of stannylcopper species. In

many instances, stoichiometric stannylcuprations require an

excess (1.3–4 equiv) of reagent for the efficient consumption of

starting material. The reaction of the mixed higer order cuprate

(e.g., Bu3Sn(Bu)Cu(CN)Li2, Bu3Sn(Me)Cu (CN)Li2) with several

monosubstituted alkynes lead regioselectively to the product of

syn addition in which the tin moiety is bound to the less hindered

acetylenic carbon. In terms of reaction scope, the reaction works

well for acetylene itself, for terminal alkynes, propargyl systems,

enynes, carbonyl-conjugated alkynes, and even for internal

alkynes, though yields are lower in this last case. Depending on

the substrate studied, a simple pre-association of the

organometallic derivative with an additional polar functional

group in the vicinity of the reaction center may completely change

the stereochemical outcome of the reaction.

Copper sources are the most popular choice for catalysts in

transition metal-catalyzed stannylmetalation, with the second

metal often being Al, Zn, Mg, etc.21 Although terminal alkynes

undergo stannylmetalation with a high degree of regio- and

stereocontrol, internal alkynes usually require the presence of

some activating group such as an ester, to achieve useful control.

Reactions utilizing tin-based reagents in which the metal is Al,

Mg, Zn, or Cu often require a two- or three-fold excess of the

reactant to achieve high consumption of the alkyne. Most of the

excess of organotin reagents is converted to hexaalkylditins, which

often complicate product isolation.184 In addition to the inherent

bias in the bimetallic reagent, the regio- and stereochemical

outcome of the reaction may be influenced by the catalyst and the

reaction conditions. A stereo-directing effect through

intramolecular coordination also plays a fundamental role in

stannylmetalation reactions.

Palladium(II) catalysts have also been used in the stannylation of

alkynes.185-186 The regiochemistry of the transition metal-catalyzed

stannylmetalation depends on a number of factors including the

metal partner, catalyst, solvent and other additives. In some

instances, the use of copper or palladium as the catalyst in the

stannylmetalation of terminal aliphatic and aromatic alkynes may

prove to be complementary.186 The comparison of the palladium-

catalyzed stannylmetalation to the hydrostannation-based process

offers important advantages to the latter process in view of

protocol simplicity, reagent preparation, and waste products.

Carbostannation of terminal alkynes,187-189 which allows the

simultaneous formation of C–C and C–Sn bonds is also a useful

method for the generation of stereo- and regio- defined

alkenylstannanes. This catalytic method is best achieved under Pd-

or Ni-catalysis and occurs with cis-stereoselectivity, furnishing

mainly the constitutional isomer in which the stannyl group resides

at the less hindered carbon, though the reaction of ynoates and

ynones shows the opposite regioselectivity. In many instances, the

carbostannation of terminal alkynes is complementary to the

conventional hydrostannation of internal alkynes because of the

formation of different constitutional and stereoisomers.

Carbostannation of internal alkynes offers unique advantages to

the hydrostannation-based process in that it allows access to

structurally complex trisubstituted alkenylstannanes having

alkynyl, alkenyl or acyl groups. These compounds serve as

versatile precursors for the synthesis of various tetrasubstituted

alkenes that are found in many important pharmaceuticals and

bioactive natural products.

6. Experimental conditions.

Organotin hydrides (e.g., Bu3SnH, Ph3SnH), in general, are toxic

and should be handled with care in a fume hood, and that

protective clothing and gloves are worn at all times. Care must

also be taken in using appropriate waste disposal procedures.

The highest toxicity is observed in triorganotin compounds,

whereas diorganotin and monoorganotin compounds show

successively lower toxicity. 190,191 The toxicity of tetraorganotin

compounds is low; however under environmental conditions they

will decompose to toxic triorganotins.192 The organic group

attached to tin also plays a significant role in the toxicity.

Triethyltin compounds are the most toxic, followed by methyl,

propyl, and butyl.190 Trioctyltin compounds have very low

toxicity, while triphenyl and tricyclohexyltin compounds show

considerable toxicity.190

Trimethyltin hydride (bp = 59 °C) is unstable to oxidative and

photolytic processes; it is not commercially available and best used

immediately upon synthesis. Its preparation involves the reaction

of LiAlH4 with Me3SnCl in ethereal solvents. Highest yields are

obtained by using high boiling solvents such as bis(2-ethoxyethyl)

ether. Me3SnH is a quite toxic reagent and should be used with

utmost care; its use in hydrostannation reactions generated as side-

product hexamethylditin, a volatile and highly toxic compound

upon ingestion, inhalation, or skin contact.

Commercially available as colorless liquids, tributyl- and

triphenyltin hydrides can be prepared by reduction of

bis(tributylltin) oxide or bis(triphenyltin) oxide with

polymethylhydrosiloxane, respectively.193 The most commonly

used reagent tributyltin hydride has also been generated in situ

from Bu3SnCl and polymethylhydrosiloxane.55,150,194,195 Organotin

hydrides can be stored for several months, and are easily repurified

by Kugelrohr distillation (oil-pump vacuum) before use. They

decompose slowly at rt and are best stored at 0 °C or below

(Ph3SnH solidifies in a refrigerator). Decomposition is catalyzed

by air, silicone grease, metallic surfaces, amines and, in the case

of triphenyltin hydride, by light. It should be kept in brown bottles

away from light and air. Manipulations of the compound are

usually best done in an inert atmosphere.

Concerns over the toxicity of organotin reagents, products and

byproducts, and difficulties associated with the purification of

product mixtures containing organotin residues represents a major

drawback for use of tin-mediated reactions, especially when

testing the biological activity of the products is foreseen.

Numerous approaches and methodologies limiting or avoiding

contamination by organotin residues have been reviewed very

recently.196

Transition-metal catalyzed hydrostannation reactions should be

carried under an inert atmosphere using anhydrous conditions. The

reactions are usually carried out by the dropwise addition of

R3SnH to a stirred solution of the catalyst and substrate in order to

minimize the undesired hexabutyldistannane side-product

formation by maintaining a low concentration of tin hydride.

Toward the end of the addition, the originally light yellow solution

abruptly turned orange-brown then dark-brown, and H2 evolution

was observed, signaling the formation of (Bu3Sn)2.

Protodestannation of alkenylstannanes is often a problem during

purification on silica gel giving low isolated yields. This drawback

may be limited or even avoided by using basic or neutral alumina

or triethylamine-treated silica gel.

The Table below (Table 1) provides the chemist an overview of

selected, efficient and general procedures, which can be used as

guides to search for “first-attempt” reaction conditions for a

planned transformation. Since its first synthesis,197 Bu3SnH has

been the most commonly used reagent for any hydrostannation due

to its availability, ease of handling, and reactivity. It should be

noted that the R group attached to the tin atom affects not only the

reactivity but also the stereoselectivity of the tin hydride addition.

Trimethyltinhydride has been used but its volatility and toxicity

make it unattractive for use. The reaction of Ph3SnH with alkyne

is more sluggish than its tributyl counterpart, and the resulting

vinyltriphenylstannane product has a critical drawback to metal-

catalyzed Stille coupling reactions due to the difficulty of

discriminating the transfer of the vinyl and phenyl groups.198

Strategies to generate organotin hydrides in situ so as to carry out

hydrostannation of alkynes in more benign ways have been also

reported.55,150,194,195 The protocol involving in situ generation of

Bu3SnH from the reduction of Bu3SnX with

polymethylhydrosiloxane (PMHS) is general and can be applied to

a wide array of terminal alkynes in free radical and palladium-

catalyzed hydrostannations, producing alkenylstannanes in good

to excellent yields. An elegant demonstration is the combination

of PMHS, aqueous KF, and catalytic amounts of Bu3SnCl in the

presence of a terminal alkyne, together with a catalytic amount of

Pd2dba3/TFP, and iodobenzene effects a one-pot

hydrostannation/Stille coupling sequence of the in situ formed

alkenylstannane.55

Table 1. General reaction conditions for alkyne hydrostannation.

The radical-induced hydrostannation of alkynes typically requires

heating at 60-80 °C in the presence of a catalytic amount of AIBN.

The use of triethylborane (vs AIBN) as initiator142 at room

temperature may improve the selectivity, but the scope of this

method is generally limited to the synthesis of

vinyltriphenylstannanes.141 Ultrasound-promoted radical

hydrostannation of terminal alkynes was found to proceed > 100

times faster than those without it at temperatures as low as -50

°C.Erreur ! Signet non défini. In all instances, reactions may be carried out

in nonpolar (e.g., toluene, benzene) as well as polar solvents (e.g.,

THF). In contrast to radical-induced processes, the Lewis acid

(e.g., ZrCl4) promoted hydrostannation of alkynes requires the use

of nonpolar solvents such as toluene or hexane at 0 °C for

obtaining high stereoselectivity and yield.50

In transition metal-catalyzed reactions, palladium complexes are

the catalyst of choice for hydrostannation of alkynes if E-

alkenylstannanes are desired. In addition to the most widely used

palladium complexes Pd(PPh3)4 and PdCl2(PPh3)2, many other

palladium sources, with or without phosphine ligands, that have

been successfully employed including Pd(OAc)2/PPh3,199

Pd(OH)2/C,24 PdCl2(dppe),62 Pd2(dba)3/PAr3,84 or

Pd2(dba)3/Cy3PHBF4.54 Contrary to early work,23 the type of ligand

used dramatically affects the regioselectivity of Pd-catalyzed

hydrostannation of terminal alkynes.54 In all these instances, THF

is the most commonly used solvent, although other solvents (e.g.,

EtOAc, Et2O, toluene, etc.) may be used, but they have modest

impact on the regioselectivity with increasing solvent

polarity.Erreur ! Signet non défini. Other metals such as cobalt,

molybdenum, nickel, platinum, rhodium, ruthenium, and tungsten

have been employed as well, but only those metal complexes (e.g.,

Mo, Ru) leading to different selectivities are reported in Figure 2.

7. Conclusion.

- or -Vinyl stannanes, easily prepared by hydrostannation of

alkynes, are very useful substrates in organic chemistry and in

complicated total synthesis. Using metal-catalysis were Pd-

24 catalysts predominated, the addition of tin hydride on the triple

bond occurred in a syn-fashion to give (E)-vinyl adducts as major

or sole products. On the contrary, in the presence of Lewis acids,

under radical conditions or using Ru-based complexes, the tin

addition on the triple bond occurs in anti for different reasons

(electronic, steric, thermodynamic,…). The problem of

regioselectivity of the tin addition on alkyne triple bond is

probably more complicated because depending of alkyne

substrates even if a variety of methodologies reported in this

review led to a single vinyl stannane isomer useful in complicated

syntheses.

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